UC Merced

Alzheimer’s disease (AD) is the leading cause of dementia among elderly in the United States. There is no effective treatment available, in part due to lack of understanding of the full spectrum of the disease mechanisms. Brain is structured in highly heterogeneous and complex way, and the number of different cell lineages, such as neurons, astrocytes, microglia, oligodendrocytes, perivascular macrophages, and capillary endothelial cells, interact with each other and functionally integrate into one highly hierarchical and organized unit. Traditionally, neurodegeneration has been centered for investigation on neurodegenerative diseases like AD. However, recent rapidly growing evidence strongly implicates the pathogenic involvement of non-neuronal cell lineages, such as astrocytes and microglia, and this work may uncover key disease mechanisms. The purpose of this dissertation is to elucidate the role of glutamate transporter 1 (GLT-1) primarily expressed in astrocytes in the progression or initiation of AD pathology. In humans, its loss is evident even in early or prodromal stages of AD and correlates well with cognitive impairment. The loss of GLT-1 causes glutamate dyshomeostasis in the synaptic cleft, which eventually leads to glutamate-induced excitotoxicity and neurodegeneration. While glutamate excitotoxicity has long been a suspected cause of progressive neurodegeneration in AD, it remains unclear whether the loss of the glutamate transporter directly contributes to the pathological buildup of amyloid β (Aβ) and neurofibrillary tau tangles (NFTs) - two key pathological hallmarks of AD. Thus, we hypothesize that the Aβ-induced GLT-1 downregulation links Aβ pathology to tau pathology, synaptic loss, and cognitive decline. To test this hypothesis, we utilized both in vitro and in vivo models of AD and thoroughly performed biochemical and histopathological examinations. We show an age-dependent decrease of GLT-1 in animal models and GLT-1 decrease in human hippocampal samples. In addition, pharmacological restoration of GLT-1 can ameliorate AD-like pathology in an animal model of AD. We also present a possible molecular mechanism that regulates GLT-1 independent of Aβ. The contribution of this research includes a better understanding on the role of astrocyte dysfunction in the early stages of AD and its consequences on the progression of the disease.